ELIGIBILITY CRITERIA:
Disease: B-Chronic Lymphocytic Leukemia (CLL) Small Lympho(plasma)cytic Lymphoma (B-SLL, B-LPL).
Disease Status: a) Relapse/progression after fludarabine and at least one other salvage regimen. (Section 2.1.7) b) Relapse/progression after autologous HSCT.
Disease: Prolymphocytic Leukemia (PLL) T-CLL.
Disease Status: a) T-PLL: Treatment failure after Campath-1H and at least one other regimen (Section 2.1.7) b) B-PLL: Treatment failure after fludarabine and at least one other salvage regimen (Section 2.1.7).
Disease: Hodgkin's Lymphoma.
Disease Status: a) Primary treatment failure ineligible for autologous HSCT. Relapse/progression after autologous HSCT.
Disease: Follicular Lymphoma, Marginal Zone Lymphomas (splenic, nodal, or extranodal/MALT type).
Disease Status: a) Chemotherapy-refractory disease b) Relapse after greater than or equal to 2 prior regimens c) Relapse/progression after autologous HSCT.
Disease: Burkitt or Acute Lymphoblastic Lymphomas.
Disease Status: a) High-risk disease in remission b) Primary refractory disease c) Recurrent disease d) Relapse/progression after autologous HSCT.
Disease: Diffuse Large B-cell Lymphoma, Follicular Large cell Lymphoma, Peripheral T-cell Lymphoma, mantle cell lymphoma, Anaplastic Large Cell Lymphoma.
Disease Status: a) Primary refractory disease. b) Relapse/progression after autologous HSCT after autologous HSCT c) Stable disease or better response to last therapy.
Disease: Cutaneous T-cell Lymphomas (Mycosis Fungoides, Sezary Syndrome)
Disease Status: a) greater than or equal to Stage III b) Disease progression greater than or equal to 2 prior regimens, including at least one systemic therapy.
Disease: Multiple Myeloma
Disease Status: a) Relapse/progression after autologous HSCT. b) Plasma cell leukemia c) Adverse cytogenetics: del(13q) or 11q translocation.
Disease: Acute Myelogenous Leukemia
Disease Status: a) In first complete Remission with high-risk cytogenetics, b) Primary induction failure. c) In second or greater complete remission. d) Secondary AML. (Section 2.1.2.3) e) In first complete Remission with hyperleukocytosis at diagnosis as defined in 2.1.2.4.
Disease: Acute Lymphocytic Leukemia.
Disease Status: a) First Complete Remission, with high-risk cytogenetics. b) Primary induction failure. c) Second or greater complete remission.
Disease: Myelodysplastic Syndrome
Disease Status: a) RAEB I or II. b) High-risk ISS. c) Secondary MDS
Disease: Myeloproliferative disorders (Idiopathic myelofibrosis, polycythemia vera, essential thrombocytosis, chronic myelomonocytic leukemia, agnogenic myeloid metaplasia).
Disease Status: a) Agnogenic myeloid metaplasia with adverse-risk features (Section 2.1.5) b) Polycythemia vera or essential thrombocythemia in transformation to secondary AML.
Disease: Chronic Myelogenous Leukemia
Disease Status: Chronic phase CML (Section 2.1.10)
Accelerated phase CML
Not eligible for myeloablative allogeneic HSCT.
2.1.1 - Diagnosis of hematologic malignancy and at least one of the criteria in the Disease Status column as specified in the table above.
2.1.2 - Recipients with AML in CR1 must have one of the following:
2.1.2.1 - Adverse cytogenetics with residual disease detectable by flow cytometry, cytogenetic analysis, FISH, or PCR. Adverse cytogenetics in AML are defined as complex karyotype (greater than or equal to 3 abnormalities); inv(3) or t(3;3); t(6;9); t(6;11); monosomy 7; trisomy 8, alone or with an abnormality other than t(8;21), t(9;11), inv(16) or t(16;16); or t(11;19)(q23;p13.1)
2.1.2.2 - Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy.
2.1.2.3 - Secondary AML, defined as AML related to antecedent MDS, MPD, or cytotoxic chemotherapy.
2.1.2.4 Hyperleukocytosis, WBC greater than or equal to 100,000, at diagnosis.
2.1.3 - Recipients with ALL in CR1 must have one of the following:
2.1.3.1 - Adverse cytogenetics or residual disease detectable by flow cytometry, cytogenetic analysis, FISH, or PCR. Adverse cytogenetics in ALL are defined as translocations involving t(4;11), t(1;19), t(8;14), 11q23, t(9;22) or bcr-abl rearrangement or complex cytogenetic abnormalities.
2.1.3.2 - Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy [93].
2.1.4 - Patients with Cutaneous T-cell Lymphomas (e.g. mycosis fungoides, Sezary syndrome) must have:
2.1.4.1 - Stage III or greater disease
2.1.4.2 - Disease which has progressed on or failed to respond to at least 2 therapies including one systemic therapy.
2.1.5 - Recipients with agnogenic myeloid metaplasia must have at least 2 of the following features:
2.1.5.1 - Hemoglobin less than 10 g/dl, or greater than 10 g/dl with transfusion dependence.
2.1.5.2 - WBC less than 4,000 or greater than 30,000/mm(3) or requires cytoreductive therapy to maintain.
2.1.5.3 - WBC less than 30,000/mm.
2.1.5.4 - Abnormal cytogenetics including plus 8, 12p-.
2.1.6 - Recipients with primary or secondary acute leukemia, refractory anemia with excess blasts (RAEB), CML, or other eligible diagnosis in transformation to acute leukemia must have less than or equal to 5percent blasts in bone marrow and no circulating blasts in peripheral blood at study entry. Recipients who do not meet these criteria may be re-evaluated for study eligibility after receiving standard induction therapy for acute leukemia and determined to be in remission.
2.1.7 - For recipients with CLL or PLL, treatment failure for a specified therapy is defined as relapse within 6 months or failure to achieve remission. Recipients who are ineligible for a specified therapy (e.g., due to refractory cytopenias) may be considered for enrollment in this protocol.
2.1.8 - For patients with non-Hodgkin's lymphoma, must be determined to have at least stable disease to last therapy.
2.1.9 - For patients with chronic phase chronic myelogenous leukemia, patient's disease must have evidence of never responded to or progressed after receiving a tyrosine-kinase inhibitor (e.g. imatinib mesylate).
2.1.10 - Patients with accelerated phase chronic myelogenous leukemia, may have less than or equal to 10 percent blasts in the peripheral smear or bone marrow at study entry.
2.1.11 - Patients 18 - 69 years of age.
2.1.12 - Patient or legal guardian must be able to give informed consent.
2.1.13 - All previous cytotoxic chemotherapy must be completed at least 2 weeks prior to study entry. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or less, unless specified elsewhere in Section 2.1.
2.1.14 - ECOG performance status equal to 0, 1, or 2, and Karnofsky performance status greater than or equal to 60 percent.
2.1.15 - Life expectancy of at least 3 months.
2.1.16 - Patients with acute leukemia must be in hematologic remission, defined as less than or equal to 5percent blasts present in both blood and bone marrow.
2.1.17 -Left ventricular ejection fraction greater than 45 percent by either MUGA or 2-D echo, obtained within 28 days of enrollment. Patients who have a prior cumulative anthracycline dose greater than 450 mg/m(2) will also have a cardiology consult to determine if further anthrracycline administration is an absolute contraindication in patients who may require induction chemotherapy with EPOCH-F.
2.1.18 - DLCO greater than 50 percent of the expected value when corrected for Hb, obtained within 28 days of enrollment.
2.1.19 - Creatinine less than or equal to 1.5 mg/dl and creatinine clearance greater than or equal to 50 ml/min/1.73 m(2).
2.1.20 - Serum total bilirubin less than 2.5 mg/dl, and serum ALT and AST values less than or equal to 2.5 times the upper limit of normal. Patients with elevations of serum total bilirubin up to 10 mg/dl and/or ALT or AST up to 10 times the upper limit of normal may be considered for participation if such elevations are thought to be due to liver involvement by malignancy. However, in these latter patients, if these values do not decrease to less than or equal to 2.5 times the upper limit of normal during induction chemotherapy, such patients will not be eligible for the transplant phase of the protocol, and will thus be taken off study.
2.1.21 - Minimum absolute neutrophil count of 1,000 cells/microliter and minimum platelet count (without transfusion) of 20,000/mm(3). Values below these levels may be accepted at the discretion of the PI or study chairperson, if thought to be due to bone marrow involvement by malignancy.
2.2 - Exclusion Criteria - Recipient
2.2.1 - Active infection that is not responding to antimicrobial therapy.
2.2.2 - Active CNS involvement by malignancy (patients with known positive CSF cytology or parenchymal lesions visible by CT or MRI).
2.2.3 - Progressive disease within 8 weeks of prior therapy or within 12 weeks after prior autologous stem cell transplantation.
2.2.4 - Active or recent second malignancies unless they have undergone potentially curative therapy for that malignancy and (1) have had no evidence of that disease for 5 years, and/or (2) be deemed at low risk for recurrence (less than or equal to 20 percent at 5 years).
2.2.5 - HIV infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.
2.2.6 - Chronic active hepatitis B. Patients may be hepatitis B core antibody positive but must be surface antigen negative and without evidence of active infection.
2.2.7 - Hepatitis C infection with evidence of cirrhosis.
2.2.8 -Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception (section 4.4). The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.
2.2.9 - Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.
2.2.10 - History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent (as determined by principal investigator or lead associate investigator).
2.2.11 - No available 10/10 matched unrelated donor.
2.2.12 - Available 10/10 allele matched donor is unwilling to donate PBSC, and no alternate donor is found.
2.3 - Inclusion Criteria - Donor:
2.3.1 - General donor inclusion criteria specified in the NMDP Standards (19th Edition). (Appendix D)
2.3.2 - The evaluation of donors shall be in accordance with existing NMDP Standard Policies and Procedures (Appendix D).
2.3.3 - Volunteer unrelated donor matched at HLA-A, B, C, DRB1, and DQ loci by high resolution typing (10/10 allele match) are acceptable donors.
2.3.4 - Ability to give informed consent.
2.3.5 - Age 18 years or older.
2.3.6 - Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody negative. This is to prevent the possible transmission of these infections to the recipient.
2.4 - Exclusion Criteria - Donor:
2.4.1 - Donor exclusion will be in accordance with existing NMDP Standards (19th Edition). (Appendix D)
2.4.2 - In addition to NMDP donor exclusion criteria, for the purposes of this protocol, donors who are unwilling to donate PBSC and only wish to pursue a bone marrow donation will be excluded. An alternate donor will be selected if possible, but in the event that no alternate donor is available, the patient will be removed from the trial.
2.4.3 - Current treatment with lithium.
2.4.4 - Presence of sickle hemoglobin as demonstrated by appropriate testing such as hemoglobin electrophoresis.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 01/13/2009